Chronic post-surgical pain (CPSP) represents a pain syndrome that interferes with postoperative daily activities and affects recovery of body functions, posing a heavy social and economic burden. Its pathogenesis is complex and unclear, which causes difficulties in treatment. Current research suggests that CPSP is influenced by genetic, psychosocial, emotional, and cognitive factors and is associated with complex neurological modulation. This review briefly introduces the definition and epidemiology of CPSP. Based on the genetic susceptibility and the interaction of epigenetic factors, gut microbes, environment, and neuro-modulatory system, we mainly addressed the pathogenesis of CPSP. The aim of this review is to provide new ideas for basic medical research and clinical practice.